732MO The combination of ICT01, a γ9δ2 T cell-activating mAb, plus pembrolizumab induces a broad antitumor immune response and disease control in patients with CPI-failure melanoma, NSCLC and bladder cancer: EVICTION trial

Abstract

ICT01, an anti-BTN3A mAb, activates γ9δ2 T cells that orchestrate a robust antitumor immune response of the innate and adaptive immune systems that leads to solid tumor infiltration of γ9δ2 T cells, CD8 T cells, and NK cells. (ESMO 2021, #9580) This immune-remodeling by ICT01 when combined with pembrolizumab unleashes the newly-activated, PD-1 expressing γ9δ2 and CD8 T cells that provide a novel, complementary combination immunotherapy regimen for CPI-failure patients that remain a large unmet medical need. In the combination arm of the EVICTION Trial, patients with advanced, metastatic melanoma, bladder cancer, or NSCLC who failed ≥1 prior CPI were treated with ICT01 plus pembrolizumab (200 mg IV Q3W). i/RECIST was conducted every 8 weeks for efficacy (1° Disease Control Rate (DCR) and 2° Overall Response Rate (ORR)) in evaluable patients (recieved 3 cycles and had a Wk 8 i/RECIST). Blood samples were collected for ICT01 target occupancy, immunophenotyping and cytokine analysis (IFNg, TNFa, IL-1b/2/4/6/8/10/12/13). Tumor biopsies (baseline, Day 28) were used for IHC of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling. Overall, ICT01 + pembro was considered safe and well-tolerated across a range of ICT01 doses (700 mcg - 200 mg, n=36), without any DLTs. Activation & migration of all circulating γ9δ2 T cells was observed 30 min post dose that returned to baseline only at doses ≤7 mg. NK and CD8 T cell activation and margination was observed 24h post dose at doses of ICT01 ≥ 7 or ≥ 20 mg, respectively. 10- to 100-fold increases in IFNγ, TNFα and CXCL10 were observed for 24h post dose. Intra-tumoral γδ, CD3, CD3+Ki67+, CD8 and CD8+ Ki67+ cell densities increased as did gene signatures for intratumoral inflammation (ImmunoSign21, IFNγ response, T cell activation). Efficacy Evaluable (n=24): 6 Melanoma: 50% DCR, 33% ORR; 11 NSCLC: 36% DCR, 9% ORR; 6 Bladder: 33% DCR, 17% ORR. The 3 melanoma responders were IPI/Nivo refractory, with 2 PRs achieved at 2 & 20 mg in pts with high baseline γ9δ2 T cell counts. ICT01 plus pembro is a novel immunotherapeutic approach worth further study in CPI failure pts.